The present disclosure relates to novel modulators of the insulin-insulin receptor signaling complex in the treatment or prevention of hypoglycemic disease states and conditions characterized by abnormal production and/or utilization of insulin, insulin analogues, or insulin mimetic s.
Insulin is the major hormone for lowering blood glucose levels. The first step in insulin action is the binding of the hormone to the insulin receptor (INSR), an integral membrane glycoprotein, also designated as CD220 or HHFS. When insulin binds to the INSR, the receptor is activated by tyrosine autophosphorylation and the INSR tyrosine kinase phosphorylates various effector molecules, including the insulin receptor substrate-1 (IRS-1), leading to hormone action (Ullrich et al, Nature 313: 756-761, 1985; Goldfine et al, Endocrine Reviews 8: 235-255, 1987; White and Kahn, Journal Biol. Chem. 269: 1-4, 1994). IRS-1 binding and phosphorylation eventually leads to an increase in the high affinity glucose transporter (Glut4) molecules on the outer membrane of insulin-responsive tissues, including muscle cells and adipose tissue, and to an increase, therefore, in the uptake of glucose from blood into these tissues. Glut4 is transported from cellular vesicles to the cell surface, where it then can mediate the transport of glucose into the cell and a decrease in blood glucose levels.
Abnormal increases in insulin secretion can lead to profound hypoglycemia or low blood sugar, a state that may result in significant morbidities including epilepsy and cerebral damage. Drug-induced hypoglycemia can result from administration of sulfonylurea drugs or from an overdose of insulin. A number of rare medical conditions feature non-drug-induced, endogenous hyperinsulinemic hypoglycemia, i.e., low blood glucose caused by the body's excessive production of insulin. These conditions include congenital hyperinsulinism, insulinoma, and hyperinsulinemic hypoglycemia following gastric bypass surgery.
Iatrogenic hypoglycemia describes the condition and effects of low blood glucose caused by administration of either excessive insulin or its analogues, or medications that stimulate endogenous insulin secretion. Iatrogenic hypoglycemia, fundamentally but not exclusively the result of treatment with an insulin secretagogue or insulin, is a major limiting factor in the glycemic management of diabetes. Iatrogenic hypoglycemia causes recurrent morbidity in most people with T1DM and many with advanced T2DM, and is sometimes fatal. Recurrent episodes of hypoglycemia impair the body's defenses against subsequent falling plasma glucose concentrations and thus cause a vicious cycle of recurrent hypoglycemia.
Hypoglycemia results in a variety of symptoms including; lack of coordination, confusion, loss of consciousness, seizures, and even death.
Most episodes of mild hypoglycemia are effectively self-treated by ingestion of glucose tablets or other carbohydrate containing drinks or snacks. More severe symptomatic hypoglycemia also can be treated with oral carbohydrate ingestion. However, when the hypoglycemic patient cannot take oral glucose supplements, because of confusion, unconsciousness or other reasons, parenteral therapy is required. As a non-hospital rescue procedure, injection of the hyperglycemic hormone, glucagon, is sometimes employed, either subcutaneously or intramuscularly by the patient himself or an associate of the patient who has been trained to recognize and treat severe hypoglycemia. In a medical setting, intravenous glucose is the standard parenteral therapy.
Congenital hyperinsulinism (CHI) comprises a group of genetic disorders that are characterized by recurrent episodes of hyperinsulinemic hypoglycemias due to unregulated secretion of insulin by the pancreatic β-cells (Arnoux J., et al. Orphanet Journal of Rare Diseases 6:63 (2011); Yorifuji T., Ann Pediatr Endocrinol Metab 19:57-68 (2014). CHI is the most common cause of hyperinsulinemic hypoglycemia in neonatal, infant and childhood periods and is usually diagnosed within the first two years of life. Histopathologically, CHI can present in either diffuse or focal forms. In the diffuse form, all pancreatic β-cells are affected, whereas in focal forms, lesions of abnormal β-cells are (usually) restricted to small areas of the pancreas. The most common known causes of CHI are loss-of-function mutations in the genes encoding SUR1 and Kir6.2, subunits of the ATP-sensitive potassium channel (KATP channel), involved in the secretion of insulin in pancreatic β-cells.
Post-prandial hypoglycemia (PPH) has recently been observed as a side effect or complication of gastric bypass surgery (Singh et al., Diabetes Spectrum 25: 217-221, 2012; Patti et al., Diabetologia 48:2236-2240, 2005; Service et al. N Engl J Med 353:249-254, 2005), including after the common procedure of Roux-en-Y gastric bypass (RYGB). A commonly observed side effect of gastric bypass surgery is “dumping,” which is a consequence of the ingestion of simple sugars and rapid emptying of food into the small intestine. This is often characterized by vasomotor symptoms (e.g., flushing, tachycardia), abdominal pain, and diarrhea (Singh et al., Diabetes Spectrum 25: 217-221, 2012; Mathews et al., Surgery 48:185-194, 1960). Late dumping can occur up to a few hours after eating and results from the insulin response to hyperglycemia resulting from rapid absorption of simple sugars from the proximal small intestine. In contrast to dumping, which is noted soon after surgery and improves with time, hyperinsulinemic hypoglycemia presents several months to years (usually around 1 year, up to 3 years) after gastric bypass surgery. This syndrome is differentiated from dumping by onset of severe postprandial neuroglycopenia, which is typically absent in dumping, as well as pancreatic nesidioblastosis (islet cell enlargement, β-cells budding from ductal epithelium, and islets in apposition to ducts). Unlike with dumping, nutrition modification does not alleviate the symptoms of post-prandial hypoglycemia (PPH).